AU2005263754B2

AU2005263754B2 - A pharmaceutical composition comprising gabapentin

Info

Publication number: AU2005263754B2
Application number: AU2005263754A
Authority: AU
Inventors: Alessandra De Lazzari; Alessandro Grassano; Luca Rampoldi
Original assignee: Zambon Group SpA; Zambon SpA
Current assignee: Zambon Group SpA
Priority date: 2004-07-20
Filing date: 2005-07-19
Publication date: 2010-09-23
Anticipated expiration: 2025-07-19
Also published as: JP5022896B2; BRPI0513566B8; CA2573985C; HRP20120937T1; IL180631A0; EP1784174B1; ES2394506T3; CA2573985A1; AU2005263754A1; PT1784174E; JP2008506751A; SI1784174T1; US20080058420A1; EA012081B1; BRPI0513566B1; ITMI20041447A1; DK1784174T3; IL180631A; WO2006008295A1; EP1784174A1

Description

WO 2006/008295 PCT/EP2005/053473 1 A PHARMACEUTICAL COMPOSITION COMPRISING GABAPENTIN Description The present invention relates to pharmaceutical compositions. In particular, the 5 invention relates to a pharmaceutical composition comprising gabapentin. Gabapentin is the common name of I-aminomethyl-l-cyclohexan-acetic acid, a known drug with anti-epileptic activity, also effective in the treatment of neuropathic pain. It is known that the formation of lactam with formula: 10 0 FIN 15 as a degradation product in the process for preparing and storing gabapentin is a drawback because of the toxicity of the lactam. In the past, some attempts have been made to contrast the formation of the undesired lactamic byproduct and thus stabilise pharmaceutical compositions containing gabapentin. 20 The U.S.A. patent No. 6,054,482 in the name of G6decke AG appears to solve the problem of favouring the conversion of less than 0.2% of gabapentin to the corresponding lactam, in a formulation whose initial lactam content is less than 0.5%, maintained for one year at 25"C and 60% relative humidity, thanks to a presence of anions of mineral acid below 20 ppm and of excipients that do not 25 promote gabapentin dehydration. The same patent also lists a series of additives to be avoided in the composition because they promote the formation of lactam. They arc: modified maize starch, sodium croscarmelose, glycerol behenic acid ester, methacrylic acid co-polymers (type A and C), anion exchange resins, titanium dioxide, silica gcl and PEG with low molecular weight. 30 On the other hand, U.S.A. patent No. 6,531,509 in the name of Teva Pharmaceuticals Industries Ltd. states that the conditions supposed to assure stability, described in the -2 aforementioned Godecke AG patent, are technically unnecessary to achieve stability. According to the Teva patent, not only stable gabapentin compositions can be obtained even when the mineral acid anion content exceeds 20 ppm, but in fact it is possible to use as preferred excipients those excipients that, according to the Gadecke patent, promoted 5 the lactamic degradation of gabapentin. The patent application No. WO 02/26263 by Sigmapharm describes stable gabapentin compositions containing a stabiliser that comprises a compound able to reduce ionic force, and at least 20 ppm of a mineral acid anion. The stabilisers belong to the following classes: volatile alcohols, non-volatile alcohols, 10 non-volatile liquids, water miscible solids or liquids, water immiscible solids or liquids, liquid or solid surfactants, anti-oxidants, ketones or aldehydes. It is readily apparent that not only the conflicting teachings of the aforementioned prior art are useless in solving the problem of lactam degradation in gabapentin formulations, but they are also likely to generate some confusion in a person skilled in the art. 15 Therefore, the ability to identify excipients suitable to control the formation of the lactamic impurity should be considered surprising in view both of the difficulties faced in the past in identifying suitable excipients, and of the confusion that actually can be noted in the state of the art with respect to excipient choice. The present inventors met the need of identifying conditions that are able to control 20 gabapentin structural integrity without increasing its susceptibility to degradation to the corresponding lactamic form. The present invention provides the following items 1 to 16: 1. A stable pharmaceutical composition comprising gabapentin as active ingredient, characterised in that it also comprises a mixture of excipients capable of not promoting 25 the conversion of gabapentin into the corresponding lactamic impurity, which comprises: (i) a sliding agent which is tribasic calcium phosphate, (ii) a lubricating agent selected from hydrogenated castor oil and glyceryl behenate; and optionally (iii) a diluting agent, alone or mixed with one or more other diluting agents, 30 selected from a monosaccharidic sugar and a polysaccharidic derivative. 2388924_1 (GHMatlers) -2a 2. A composition of item 1, wherein the monosaccharidic sugar is selected from sorbitol, xylitol, mannitol, fructose, dextrose and erythritol. 3. A composition of item I or 2, wherein the polysaccharidic derivative is selected from saccharose, mannitol, isomalt, maltitol, a galactomannan, alginic acid or one of its 5 salts, a pectin, a carrageenan and maltodextrin. 4. A composition of any one of claims 1 to 3, wherein gabapentin is present in amount variable between 50% and 99% of the total by weight of the composition. 5. A composition of any one of claims 1 to 3, wherein a sliding agent is present in amount variable between 0.5% and 5% of the total by weight of the composition. 10 6. A composition of any one of claims 1 to 3, wherein a lubricating agent is present in amount variable between 0.1 % and 8% of the total by weight of the composition. 7. A composition of any one of claims 1 to 3, wherein a diluting agent is present in amount variable between 0% and 50% of the total by weight of the composition. 8. A composition of any one of claims I to 3, wherein a diluting agent is present in a 15 mixture with one or more diluting agents selected from those described in claim 2 or 3. 9. A composition of item 8, wherein the diluting agents in the mixture are sorbitol and alginic acid. 10. A composition of item 3, wherein a galactomannan is guar rubber. 11. A composition of item 3, wherein a salt of alginic acid is sodium, potassium or 20 calcium alginate. 12. A composition of item 3, wherein a pectin is citrus pectin. 13. A composition of item 3, wherein a carrageenan is the kappa, iota, lambda or ksi carrageenan, or a calcium, ammonium or potassium salt thereof. 14. A pharmaceutical composition of any one of claims I to 3, wherein the lubricant is 25 hydrogenated castor oil, and sorbitol as a diluting agent is present in a mixture with another diluting agent, which is alginic acid. 15. Use of a pharmaceutical composition of any one of claims 1 to 3, for the preparation of capsules. 16. Capsules containing a pharmaceutical composition of any one of claims I to 3. 2388924_1 (GHMatters) -2b Therefore, the present invention provides a stable pharmaceutical composition comprising gabapentin as active ingredient, characterised in that it also comprises a mixture of excipients capable of not promoting the conversion of gabapentin into the corresponding lactamic impurity, which comprises: 5 (i) a sliding agent which is tribasic calcium phosphate, (ii) a lubricating agent selected from hydrogenated castor oil and glyceryl behenate; and optionally -3- (iii) a diluting agent, alone or mixed with one or more other diluting agents, selected from a monosaccharidic sugar like sorbitol, xylitol, mannitol, fructose, dextrose and erythritol and' polysaccbaridic derivatives like saccharose, 5 mannitol, isomalt, maltitol, a galactomannan, alginic acid or one of its salts, a pectin, a carrageenan and maltodextrin. According to the present invention, a monosaccharidic sugar is, preferably, sorbitol. According to the present invention, a galactomannan is, preferably, guar rubber. According to the present invention a polysaccharide derivative is, preferably, alginic 10 acid. According to the present invention an alginic acid salt is sodium, potassium or calcium alginate, preferably sodium or calcium alginate, more preferably calcium alginate. According to the present invention, a pectin is, preferably, citrus pectin. 15 According to the present invention a carrageenan is the kappa, iota, lambda or ksi carrageenan, or a calcium, ammonium or potassium salt thereof, preferably a calcium salt. In particular, a carrageenan is, preferably, the lambda carrageenan or a calcium salt thereof. Moreover, the excipients listed above, when mixed with gabapentin even in small 20 quantities with respect to the active principle, are able to impart to the resulting mixture some favourable technological properties especially with regard to the sliding property. This advantageous property can be exploited to facilitate pharmaceutical operations that entail allocating the powders, such as the manufacture of capsules and bags, 25 without using complex technical approaches. In a preferred aspect of the present invention, a diluting agent is present in a mixture with one or more diluting agents selected from those mentioned above. Preferably, the diluting agents in the mixture are sorbitol and alginic acid. 30 WO 2006/008295 PCT/EP2005/053473 -4 A particular pharmaceutical composition according to the invention comprises gabapentin as the active ingredient, tribasic calcium phosphate as a sliding agent, hydrogenated castor oil as a lubricant, sorbitol and alginic acid in mixture as diluents. 5 In the pharmaceutical compositions according to the invention, the amount of gabapentin can vary from 50% to 99% of the total by weight of the composition, preferably from 70% to 98% of the total by weight of the composition; the amount of a sliding agent can vary from 0.5% to 5% of the total by weight of the composition, preferably from 1% to 3% of the total by weight of the composition; the amount of a 10 lubricating agent can vary from 0.1% to 8% of the total by weight of the composition, preferably from 0.5% to 6% of the total by weight of the composition; and the amount of a diluting agent can vary from 0% to 50% of the total by weight of the composition, preferably from 0% to 40% of the total by weight of the composition. 15 The pharmaceutical compositions according to the present invention can be prepared according to the classic technique suggested by the state of the art, i.e. mixing the dry powders of each ingredient in a suitable mixer and the allocation of the mixture by means of a common encapsulating machine. According to the present invention, a stable pharmaceutical composition containing 20 gabapontin is one in which the content of the corresponding lactamic impurity does not exceed 0.2% by weight of gabapentin, after being maintained for 3 months at the storage conditions of 25"C with 60% of relative humidity, and/or at 30*C with 65% of relative humidity. Some of the pharmaceutical compositions of the invention, evaluated as a 25 representative example, have demonstrated that they meet the aforementioned conditions and they can therefore be considered stable for the purposes of the present invention. Since, as stated above, the pharmaceutical compositions of the invention can be considered stable, not causing the undesired degradation of the active ingredient, 30 they can be used successfully to prepare the pharmaceutical forms for oral use of -5 gabapentin, in particular in the preparation of capsule, e.g. capsules made of hard gelatin or cllulose. Therefore, the present invention also provides the use of the pharmaceutical 5 composition as described above for the preparation of gabapentin capsules and the capsules that contain said composition. The better to illustrate, without limiting, the present invention, the following examples are now provided. Example I 10 General procedure for the paration of the pharmaceutical compositions according to the invention In a Turbula Mod. T2F mixer of the company Bachofen (Basil - Switzerland) equipped with a metallic container with a capacity of 2 litres, a mixture of powders constituted by gabapentin and by the appropriate excipients able not to promote the 15 conversion of gabapentin into the corresponding lactamic impurity, is charged for 10 minutes at mom temperature at a speed of 10 rpm. The mixture of powders thus obtained, depending on the amount of ingredients introduced, can have a composition falling within the following values: gabapcntin 50-99% of the total by weight of the composition; 20 a sliding agent 0.5-5% of the total by weight of the composition; a lubricating agent 0.1-8% of the total by weight of the composition; and a diluting agent 0-50% of the total by weight of the composition. The powders thus obtained are discharged and- they arc ready to be allocated in capsules. 25 Example 2 With the procedure described in Example 1, the following pharmaceutical compositions were prepared. The quantities of the components being expressed in % of the component out of the total by weight of the composition. Composition I 30 Gabapentin 75% WO 2006/008295 PCT/EP2005/053473 -6 Sorbitol 15% Alginic acid 4% Hydrogenated castor oil 5% 5 Tribasic calcium phosphate 1% Composition 2 Gabapentin 70% Fructose 12.5% Pectin 10% 10 Carrageenan X 5% Glyceryl behenate 0.5% Tribasic calcium phosphate 2% Composition 3 Gabapentin 90% 15 Mannitol 3% Calcium alginate 1% Hydrogenated castor oil 3% Tribasic calcium phosphate 3% Composition 4 20 Gabapcntin 95% Tribasic calcium phosphate 4% Glyccryl bchcnatc 1% Composition 5 Gabapentin 80% 25 Xylitol 10% Erythritol 1% Maltodextrin 5% Glyceryl behenate 2% Tribasic calcium phosphate 2% 30 WO 2006/008295 PCT/EP2005/053473 -7 Composition 6 Gabapentin 60% Isomalt 10% 5 Saccharose 20% Alginic acid 9% Hydrogenated castor oil 0.5% Tribasic calcium phosphate 0.5% Composition 7 10 Gabapentin 75% Dextrose 10% Guar rubber 7% Hydrogenated castor oil 6% Tribasic calcium phosphate 2% 15 Composition 8 Gabapentin 85% Maltitol 5 % Tribasic calcium phosphate 2% Glyceryl behenate 1% 20 Hydrogenated castor oil 7% Composition 9 Gabapentin 90% Sorbitol 3% Sodium alginate 1% 25 Glyceryl behenate 2% Hydrogenated castor oil 1% Tribasic calcium phosphate 3% Example 3 The pharmaceutical compositions of Example 2 were used separately to fill capsules 30 made of hard gelatine and cellulose, obtaining pharmaceutical forms of gabapentin in -8 capsules, by using an IN-CAP Model automatic encapsulating machine by the company Dott. Bonapace (Milan-Italy). It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general 5 knowledge in the art, in Australia or any other country. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or 10 addition of further features in various embodiments of the invention.

Claims

1. A stable pharmaceutical composition comprising gabapentin as active ingredient, characterised in that it also comprises a mixture of excipients capable of not promoting the conversion of gabapentin into the corresponding lactamic impurity, which comprises: 5 (i) a sliding agent which is tribasic calcium phosphate, (ii) a lubricating agent selected from hydrogenated castor oil and glyceryl behenate; and optionally (iii) a diluting agent, alone or mixed with one or more other diluting agents, selected from a monosaccharidic sugar and a polysaccharidic derivative. 10

2. A composition as claimed in claim 1, wherein the monosaccharidic sugar is selected from sorbitol, xylitol, mannitol, fructose, dextrose and erythritol.

3. A composition as claimed in claim 1 or 2, wherein the polysaccharidic derivative is selected from saccharose, mannitol, isomalt, maltitol, a galactomannan, alginic acid or one of its salts, a pectin, a carrageenan and maltodextrin. 15

4. A composition as claimed in any one of claims I to 3, wherein gabapentin is present in amount variable between 50% and 99% of the total by weight of the composition.

5. A composition as claimed in any one of claims 1 to 3, wherein a sliding agent is present in amount variable between 0.5% and 5% of the total by weight of the 20 composition.

6. A composition as claimed in any one of claims 1 to 3, wherein a lubricating agent is present in amount variable between 0.1 % and 8% of the total by weight of the composition.

7. A composition as claimed in any one of claims 1 to 3, wherein a diluting agent is 25 present in amount variable between 0% and 50% of the total by weight of the composition.

8. A composition as claimed in any one of claims 1 to 3, wherein a diluting agent is present in a mixture with one or more diluting agents selected from those described in claim 2 or 3. 30

9. A composition as claimed in claim 8, wherein the diluting agents in the mixture are sorbitol and alginic acid. 2388865_1 (GHMatters) -10

10. A composition as claimed in claim 3, wherein a galactomannan is guar rubber.

11. A composition as claimed in claim 3, wherein a salt of alginic acid is sodium, potassium or calcium alginate.

12. A composition as claimed in claim 3, wherein a pectin is citrus pectin. 5

13. A composition as claimed in claim 3, wherein a carrageenan is the kappa, iota, lambda or ksi carrageenan, or a calcium, ammonium or potassium salt thereof.

14. A pharmaceutical composition as claimed in any one of claims I to 3, wherein the lubricant is hydrogenated castor oil, and sorbitol as a diluting agent is present in a mixture with another diluting agent, which is alginic acid. 10

15. Use of a pharmaceutical composition as claimed in any one of claims I to 3, for the preparation of capsules.

16. Capsules containing a pharmaceutical composition as claimed in any one of claims I to 3.

17. A stable pharmaceutical composition comprising gabapentin as active ingredient, 15 substantially as herein described with reference to any one of the Examples.

18. Use of a stable pharmaceutical composition comprising gabapentin as active ingredient, substantially as herein described with reference to any one of the Examples.

19. Capsules containing a stable pharmaceutical composition comprising gabapentin as active ingredient, substantially as herein described with reference to any one of the

20 Examples.